Impact of Colloidal Drug-Rich Droplet Size and Amorphous Solubility on Drug Membrane Permeability: A Comprehensive Analysis.

This study aimed to investigate the impact of amorphous solubility and colloidal drug-rich droplets on drug absorption. The amorphous solubility of cilnidipine (CND) in AS-HF grade of hypromellose acetate succinate (HPMC-AS) solution was significantly reduced compared to that in non-polymer solution due to AS-HF partitioning into the CND-rich phase. In contrast, AS-LF grade of HPMC-AS has minimal effect on the amorphous solubility. The size of colloidal CND-rich droplets formed in the CND-supersaturated solution was less than 100 nm in the presence of AS-HF, while 200-450 nm in the presence of AS-LF. When the CND concentrations were near the amorphous solubility, CND membrane flux was reduced in the presence of AS-HF due to the decrease in the amorphous solubility of CND. However, the CND flux increased with the increase in CND-rich droplets, especially in the AS-HF solution. The size reduction of the CND-rich droplets led to their effective diffusion into the unstirred water layer, enhancing CND flux. In higher CND concentration regions, the CND flux became higher in the AS-HF solution than in the AS-LF solution. Thus, it is essential to elucidate the drug concentration-dependent impact of the colloidal drug-rich droplets on the drug absorption performance to optimize supersaturating formulations.

Quantitative Investigation of Intestinal Drug Absorption Enhancement by Drug-Rich Nanodroplets Generated via Liquid-Liquid Phase Separation.

Drug-rich droplets formed through liquid-liquid phase separation (LLPS) have the potential to enhance the oral absorption of drugs. This can be attributed to the diffusion of these droplets into the unstirred water layer (UWL) of the gastrointestinal tract and their reservoir effects on maintaining drug supersaturation. However, a quantitative understanding of the effect of drug-rich droplets on intestinal drug absorption is still lacking. In this study, the enhancement of intestinal drug absorption through the formation of drug-rich droplets was quantitatively evaluated on a mechanistic basis. To obtain fenofibrate (FFB)-rich droplets, an amorphous solid dispersion (ASD) of FFB/hypromellose (HPMC) was dispersed in an aqueous medium. Physicochemical characterization confirmed the presence of nanosized FFB-rich droplets in the supercooled liquid state within the FFB/HPMC ASD dispersion. An in situ single-pass intestinal perfusion (SPIP) assay in rats demonstrated that increased quantities of FFB-rich nanodroplets enhanced the intestinal absorption of FFB. The effective diffusion of FFB-rich nanodroplets through UWL would partially contribute to the improved FFB absorption. Additionally, confocal laser scanning microscopy (CLSM) of cross sections of the rat intestine after the administration of fluorescently labeled FFB-rich nanodroplets showed that these nanodroplets were directly taken up by small intestinal epithelial cells. Therefore, the direct uptake of drug-rich nanodroplets by the small intestine is a potential mechanism for improving FFB absorption in the intestine. To quantitatively evaluate the impact of FFB-rich droplets on the FFB absorption enhancement, we determined the apparent permeabilities of the FFB-rich nanodroplets and dissolved FFB based on the SPIP results. The apparent permeability of the FFB-rich nanodroplets was 110-130 times lower than that of dissolved FFB. However, when the FFB-rich nanodroplet concentration was several hundred times higher than that of dissolved FFB, the FFB-rich nanodroplets contributed significantly to FFB absorption improvement. The present study highlights that drug-rich nanodroplets play a direct role in enhancing drug absorption in the gastrointestinal tract, indicating their potential for further improvement of oral absorption from ASD formulations.

A Novel Oral Drugs Delivery System for Borneol Based on HiCap®100 and Maltodextrin: Preparation, Characterization, and the Investigation as an Intestinal Absorption Enhancer.

The objective of this study was to create a new method for delivering oral borneol (BN) drug that would improve stability. This was accomplished through microencapsulation using HiCap®100 and maltodextrin (MD), resulting in HiCap®100/MD/BN microcapsules (MCs). The HiCap®100/MD/BN MCs were evaluated in terms of encapsulation efficiency (EE%), drug loading (DL%), morphological observations, particle size distribution, Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), thermal analysis, drug degradation rate studies, and in vitro release behavior. The effect of MCs on intestinal permeability in a rat model was assessed using the model drug "florfenicol" (FF) in single-pass intestinal perfusion (SPIP) study. The relationship between MCs and P-glycoprotein (P-gp) was further investigated in comparison with verapamil (Ver). The irritation of MCs was assessed by histological analysis. The MCs in a spherical structure with micron-scale dimensions were obtained. The EE% and DL% were (86.71 ± 0.96)% and (6.03 ± 0.32)%, respectively. MCs played a significantly protective role in drug degradation rate studies. In vitro release studies indicated that the release behavior of MCs was significantly better than BN at the three-release media, and the cumulative release rate exceeded 90% in 15 min. The SPIP studies showed that MCs significantly enhanced the absorption of FF in rats. Compared with Ver, MCs were not promoted by a single inhibition of P-gp. Hematoxylin-eosin (HE)-stained images showed that MCs had no obvious irritation and toxic effects on the intestines of rats. Thus, the preparation of HiCap®100/MD/BN MCs improves the stability of BN, which has certain scientific value for the development and application of BN, and provides unique perspectives for future BN-related researches.

Optimization of a Self-microemulsifying Drug Delivery System for Oral Administration of the Lipophilic Drug, Resveratrol: Enhanced Intestinal Permeability in Rat.

Purpose: This study aimed to formulate Resveratrol, a practically water-insoluble antioxidant in a self-microemulsifying drug delivery system (SMEDDS) to improve the solubility, release rate, and intestinal permeability of the drug. Methods: The suitable oil, surfactant, and co-surfactant were chosen according to the drug solubility study. Utilizing the design of experiment (DoE) method, the pseudo-ternary phase diagram was plotted based on the droplet size. In vitro dissolution study and the single-pass intestinal perfusion were performed for the investigation of in vitro and in-situ permeability for drugs formulated as SMEDDS in rat intestine using High-Performance Liquid Chromatography. Results: Castor oil, Cremophor® RH60, and PEG 1500 were selected as oil, surfactant, and co-surfactant. According to the pseudo-ternary phase diagram, nine formulations developed microemulsions with sizes ranging between 145-967 nm. Formulations passed the centrifuge and freeze-thaw stability tests. The optimum formulation possessed an almost 2.5-fold higher cumulative percentage of in vitro released resveratrol, in comparison to resveratrol aqueous suspension within 120 minutes. The results of the in-situ permeability study suggested a 2.6-fold higher intestinal permeability for optimum formulation than that of the resveratrol suspension. Conclusion: SMEDDS can be considered suitable for the oral delivery of resveratrol according to the observed increased intestinal permeability, which could consequently enhance the bioavailability and therapeutic efficacy of the drug.

Comparison of intestinal absorption characteristics between rhubarb traditional Chinese medicine preparation and activity ingredients using in situ and in vitro model.

Objective: The intestinal absorption characteristics of active ingredients are very important for oral administration of traditional Chinese medicine (TCM) to achieve the desired therapeutic effect. However, a deeper understanding about active ingredients absorption characteristics is still lack. The aim of this study was to investigate the absorption properties and mechanism of rhubarb active ingredients in TCM preparation and pure form. Methods: The intestinal absorption behavior of active ingredients in Shenkang extract (SKE) and rhubarb anthraquinone ingredients (RAI) were investigated by in situ single-pass intestinal perfusion model. And the bidirectional transport characteristics of these active ingredients were assessed by in vitro Caco-2 cell monolayer model. Results: In situ experiment on Sprague-Dawley rats, the effective permeability coefficient values of aloe-emodin, emodin and chrysophanol in RAI were higher than those in SKE, and the value of rhein in RAI was lower than that in SKE. But the easily absorbed segments of intestine were consistent for all ingredients, whether in SKE or in RAI. In vitro experiment, the apparent permeability coefficient values of rhein, emodin and chrysophanol in RAI were higher than those in SKE, and this value of aloe-emodin in RAI was lower than that in SKE. But their efflux ratio (ER) values in SKE and RAI were all similar. Conclusion: Four rhubarb anthraquinone ingredients in SKE and RAI have similar absorption mechanism and different absorption behavior, and the microenvironment of the study models influenced their absorption behavior. The results may provide an aid for understanding of the absorption characteristics of the TCM active ingredients in complex environments and the complementarities of different research models.

Hypotonicity-Induced Increase in Duodenal Mucosal Permeability Is Regulated by Cholinergic Receptors in Rats.

BACKGROUND: The role of cholinergic receptors in the regulation of duodenal mucosal permeability in vivo is currently not fully described. AIMS: To elucidate the impact of nicotinic and muscarinic acetylcholine receptor signaling in response to luminal hypotonicity (50 mM NaCl) in the proximal small intestine of rat. METHODS: The effect on duodenal blood-to-lumen clearance of 51Cr-EDTA (i.e., mucosal permeability) and motility was studied in the absence and presence of nicotinic and muscarinic receptor agonists and antagonists, a sodium channel blocker (tetrodotoxin), and after bilateral cervical vagotomy. RESULTS: Rats with duodenal contractions responded to luminal hypotonicity by substantial increase in intestinal permeability. This response was absent in animals given a non-selective nicotinic receptor antagonist (mecamylamine) or agonist (epibatidine). Pretreatment with tetrodotoxin reduced the increase in mucosal permeability in response to luminal hypotonicity. Further, the non-selective muscarinic receptor antagonist (atropine) and agonist (bethanechol) reduced the hypotonicity-induced increase in mucosal permeability, while vagotomy was without an effect, suggesting that local enteric reflexes dominate. Finally, neither stimulating nor blocking the α7-nicotinic receptor had any significant effects on duodenal permeability in response to luminal hypotonicity, suggesting that this receptor is not involved in regulation of duodenal permeability. The effect of the different drugs on mucosal permeability was similar to the effect observed for duodenal motility. CONCLUSIONS: A complex enteric intramural excitatory neural reflex involving both nicotinic and muscarinic receptor subtypes mediates an increase in mucosal permeability induced by luminal hypotonicity.

Comparision of the phenol red, gravimetric, and synthesized mPEG-PR methods for correcting water flux using the single-pass intestinal perfusion method.

Phenol red and PEG-4000, the usual non-absorbable indicators, have non-negligible absorption problems in measuring water flux. mPEG-PR, combined phenol red with mPEG-4000, was first synthesized and could decrease absorption. However, its application has not been confirmed. The purpose of this study was to explore the applicability of mPEG-PR as a novel non-absorption indicator in the in situ single-pass intestinal perfusion (SPIP) experiment. Six model drugs (atenolol ranitidine, ibuprofen, ketoprofen, antipyrine, hydrochlorothiazide) were used to compare the accuracy of four measuring methods including phenol red, mPEG-PR, gravimetric, and non-corrected methods of correcting intestinal fluid transport. Moreover, we evaluated the correlations between the effective permeability coefficients (Peff) in rat and fraction dose absorbed (Fabs) in human, Peff in human, and apparent permeability coefficients (Papp) by the Ussing Chamber system using human tissue. Among these methods, mPEG-PR was the most reliable approach, which avoided the absorption of phenol red method and mucous shedding or water evaporation of gravimetric method. An excellent correlation was obtained between the Peff of rat and Fabs of human. Our results of this study indicated that mPEG-PR was a stable and accurate non-absorbable indicator to correct water flux in the in situ SPIP model, which could be developed to predict the human Fabs.

Study on the intestinal permeability of lamivudine using Caco-2 cells monolayer and Single-pass intestinal perfusion.

Background: The aim of this work is to investigate the intestinal permeability of lamivudine and explore its absorption mechanism. Method: Caco-2 cells monolayer and single-pass intestinal perfusion (SPIP) were selected for the investigation of lamivudine under different conditions, such as different concentration, absorption time, bidirectional transportation, and transportation with efflux transporters inhibitor. The concentration of lamivudine both in Caco-2 cells monolayer samples and SPIP samples was detected by HPLC-UV. Then the permeability parameters were calculated. Results: The established HPLC-UV method reach the requirements for detection. There is no statistically difference between absorption parameters of lamivudine both in Caco-2 cells monolayer and SPIP (P > 0.05) under different dose groups. After transportation with efflux transporters inhibitor, the efflux rate of lamivudine in three dose groups was significantly decreased from 2.67, 2.59 and 2.59 to 1.78, 1.61, and 1.81 respectively. Lamivudine exhibits an absorption mechanism of passive diffusion. Conclusion: The absorption of lamivudine may be related to efflux transporters. In addition, lamivudine is a moderate-permeability drug in Biopharmaceutics Classification System.

Synergistic effects of trans-p-coumaric acid isolated from the ethanol extract of Gynura procumbens in promoting intestinal absorption of chlorogenic acid and reversing alcoholic fatty liver disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Our previous studies found that the ethanol extract of Gynura procumbens (EEGS) reduced hepatic steatosis in alcoholic fatty liver disease (AFLD). AIM OF THE STUDY: To explore the active ingredients from EEGS and their relevant mechanism of action in alleviating alcoholic liver injuries. AIM OF THE STUDY: To explore the active ingredients from EEGS and their intestinal absorption characteristics as an approach for understanding mechanism of action in alleviating alcoholic liver injuries. MATERIALS AND METHODS: Monitored by high-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC), chemical constituents from the prepared EEGS were isolated by means of solvent extraction, repeated column chromatography, preparative HPLC and other methods, and their structures were identified based on spectroscopic methods. The in vivo intestinal absorption rate of chlorogenic acid (CA), the active component of the EEGS, both in a single form and in the EEGS were monitored by the single-pass intestinal perfusion (SPIP) method in rats. The protective effect of EEGS and its active components on alcoholic liver injuries was evaluated in the alcoholic liver injury model of C57BL/6J male mice induced by Lieber-DeCarli alcohol liquid feed. RESULTS: Three noncaffeoyl quinic acid components were isolated and identified from the EEGS, namely, 3-trans-p-coumaroyl quinic acid (0.9%), 3-cis-p-coumaroyl quinic acid (2.7%), and trans-p-coumaric acid (0.6%). In vivo intestinal absorption of CA decreased with the increase of pH value of perfusion solution in the range of 5.5-7.8. The maximum absorption percentage of CA alone was 6.7 ± 2.4%, while the maximum absorption percentage of CA in the EEGS was 16.0 ± 2.2%, which was 2.4 times higher than that of CA alone. The results of animal experiments showed that the degree of fatty liver of mice treated with EEGS was significantly lower than that of the CA, trans-p-coumaric acid, and the combination group of CA and trans-p-coumaric acid alone. CONCLUSION: The above results indicated that trans-p-coumaric acid isolated from the dried stems of Gynura procumbens assisted CA being absorbed into the body and worked together with CA to improve the function of liver lipid metabolism, reduce hepatic lipid accumulation in a mouse model of AFLD and effectively counteract alcohol-induced fatty liver disease.

The Effect of Particle Size on the Absorption of Cyclosporin A Nanosuspensions.

Background: Cyclosporin A (CsA) is a hydrophobic drug widely used as an immunosuppressant and anti-rejection drug in solid organ transplantation. On the market, there are two oral CsA formulations available containing polyoxyethylene castor oil, which can cause serious allergic reactions and nephrotoxicity. In order to eliminate polyoxyethylene castor oil, CsA was formulated into a nanosuspension. This study aimed to design an oral cyclosporin A nanosuspensions (CsA-NSs) and investigate the effect of particle size on absorption of CsA-NSs. Methods: CsA-NSs were prepared using a wet bead milling method. Particle size, morphology and crystallinity state of CsA-NSs were characterized. The in vitro dissolution, the intestinal absorption properties and pharmacokinetic study of CsA-NSs were investigated. Results: CsA-NSs with sizes of 280 nm, 522 nm and 2967 nm were prepared. The shape of CsA-NSs with smaller size was similar to that of spheres. The crystallinity of CsA in nanocrystals was reduced. The dissolution rate of CsA-NSs (280 nm) was greater than that of CsA-NSs (522 nm) and CsA-NSs (2967 nm). CsA-NSs (280 nm) showed higher absorption rate constants (Kα ) and effective permeability coefficients (Peff ) of different intestinal segments compared with that of CsA-NSs (522 nm) and CsA-NSs (2967 nm). AUC0-48h of 280 nm CsA-NSs was about 1.12-fold of that of 522 nm CsA-NSs, and about 1.51-fold of that of 2967 nm CsA-NSs. In particular, the particle size of CsA-NSs was nanoscale, and their bioavailability was bioequivalent with marked self-microemulsion (Sandimmun Neoral®). Conclusion: It is feasible to prepare CsA-NSs. The dissolution rate, gastrointestinal transport properties and the oral absorption of CsA-NSs were promoted by reducing size. Considering the cost, efficiency and energy consumption, there should be an optimal particle size range in industrial production.

Baicalin-berberine complex nanocrystals orally promote the co-absorption of two components.

Baicalin (BA)-berberine (BBR) have been proposed as the couple in the prevention and treatment of numerous diseases due to their multiple functional attributes. However, with regard to certain factors involving unsatisfactory aqueous solubility and low bioavailability associated with its clinical application, there is need for continuous researches by scientist. In this study, after successfully preparing BA-BBR complex, BA-BBR complex nanocrystals were obtained through high-pressure homogenization and evaluated (in vitro and in vivo). The particle size, distribution, morphology, and crystalline properties for the optimal BA-BBR complex nanocrystals were characterized by the use of scanning electron microscope, dynamic light scattering, powder X-ray diffraction, and differential scanning calorimetry. The particle size and poly-dispersity index of BA-BBR complex nanocrystals were 318.40 ± 3.32 nm and 0.26 ± 0.03, respectively. In addition, evaluation of the in vitro dissolution extent indicated that BA and BBR in BA-BBR complex nanocrystals were 3.30- and 2.35-fold than BA-BBR complex. Subsequently, single-pass intestinal perfusion combined with microdialysis test and oral pharmacokinetics in SD rats was employed to evaluate the in vivo absorption improvement of BA-BBR complex nanocrystals. The pharmacokinetics results exhibited that the area under curve of BA and BBR in the BA-BBR complex nanocrystals group were 622.65 ± 456.95 h·ng/ml and 167.28 ± 78.87 h·ng/ml, respectively, which were separately 7.49- and 2.64-fold than the complex coarse suspension. In conclusion, the above results indicate that the developed and optimized BA-BBR complex nanocrystals could improve the dissolution rate and extent and oral bioavailability, as well as facilitate the co-absorption of the drug prescriptions BA and BBR.

Protective Effects of Melatonin and Misoprostol against Experimentally Induced Increases in Intestinal Permeability in Rats.

Intestinal mucosal barrier dysfunction caused by disease and/or chemotherapy lacks an effective treatment, which highlights a strong medical need. Our group has previously demonstrated the potential of melatonin and misoprostol to treat increases in intestinal mucosal permeability induced by 15-min luminal exposure to a surfactant, sodium dodecyl sulfate (SDS). However, it is not known which luminal melatonin and misoprostol concentrations are effective, and whether they are effective for a longer SDS exposure time. The objective of this single-pass intestinal perfusion study in rats was to investigate the concentration-dependent effect of melatonin and misoprostol on an increase in intestinal permeability induced by 60-min luminal SDS exposure. The cytoprotective effect was investigated by evaluating the intestinal clearance of 51Cr-labeled EDTA in response to luminal SDS as well as a histological evaluation of the exposed tissue. Melatonin at both 10 and 100 µM reduced SDS-induced increase in permeability by 50%. Misoprostol at 1 and 10 µM reduced the permeability by 50 and 75%, respectively. Combination of the two drugs at their respective highest concentrations had no additive protective effect. These in vivo results support further investigations of melatonin and misoprostol for oral treatments of a dysfunctional intestinal barrier.

Exploring the Predictive Power of the In Situ Perfusion Technique towards Drug Absorption: Theory, Practice, and Applications.

Considering the broad applications and popularity, the in situ perfusion technique is an established and interesting approach to evaluate the absorption mechanisms of drug molecules in specific regions of the intestinal tract. Compared to perfusion studies in humans, this surrogate model shows several familiar characteristics making it interesting to apply this technique in rats in the non-clinical stage of drug product development. The differences in gastrointestinal (GI) anatomy and physiology between rats and humans are thoroughly discussed in the present review. Moreover, an in-depth overview of the Doluisio (i.e., closed-loop) versus the single-pass intestinal perfusion (i.e., open-loop) technique is shown. Finally, applications and future perspectives of the technique are presented.

Intestinal metabolism and absorption mechanism of multi-components in Gaultheria leucocarpa var. yunnanensis - An assessment using in situ and in vitro models, comparing gut segments in pathological with physiological conditions.

ETHNOPHARMACOLOGICAL RELEVANCE: Dianbaizhu (Gaultheria leucocarpa var. yunnanensis) as a Chinese folk medicine exerts significant treatment effects on rheumatoid arthritis (RA) with a long historical time. Our previous reports showed that the anti-rheumatic arthritis fraction (ARF) extracted and enriched from Dianbaizhu possessed good druggability, which was better than its single active ingredients. However, the intestinal transport characteristics and mechanism of ARF have not been elucidated to date. AIM OF THE STUDY: In order to illustrate the role of active ingredients of ARF in alleviating RA and promoting the development of dosage forms, the intestinal metabolism, absorption properties and mechanism of ARF in vitro and in situ models were investigated. MATERIALS AND METHODS: Firstly, after incubating with 4 intestinal segments (duodenum, jejunum, ileum, and colon), 7 key components in ARF, including MATG-B, (+)-catechin, MSTG-A, Gaultherin, chlorogenic acid, quercetin, and kaempferol were quantitatively analyzed by a high-performance liquid chromatography (HPLC). Secondly, combining the physiological and pathological rats, the in situ single-pass intestinal perfusion and in vitro everted gut sacs of rats were performed to investigate the absorption features and transport mechanisms of ARF using HPLC and HPLC-Q-TOF-MS/MS. Subsequently, in situ studies were employed to determine the effect of P-glycoprotein (P-gp) inhibitor (verapamil) on the transport characteristics of ARF in RA model rats. RESULTS: Comparing the absorption parameters of ARF incubated in different intestinal segments, data showed that the absorption of ARF in the small intestine was significantly stronger than that of the colon (P < 0.01). The number of characterized prototype components was subjected to the incubation time, drug concentration and rat body condition, but not the intestinal segments. There were no significant differences in the number of metabolites among different intestinal segments, administration concentrations and incubation time. The best small intestinal absorption site of ARF was duodenum and ileum in normal and model rats, respectively. The Peff values of 7 index compounds were all higher than 0.2 × 10-4cm/s, and the Fa values of 7 index compounds were all greater than 20% in the in situ perfusion investigation. The results showed that MSTG-B, MSTG-A and Gaultherin were likely to be substrates of P-gp as verapamil significantly enhanced their Peff and Ka values, while other ingredients were not P-gp substrates. CONCLUSIONS: The intestinal membrane permeability of ARF was good. Its intestinal absorption mechanisms mainly involved active transportation processes and passive diffusion. Besides, this report provided data support and basis for clinical development, bioavailability improvement and formulation design.

Melatonin-Activated Receptor Signaling Pathways Mediate Protective Effects on Surfactant-Induced Increase in Jejunal Mucosal Permeability in Rats.

A well-functional intestinal mucosal barrier can be compromised as a result of various diseases, chemotherapy, radiation, and chemical exposures including surfactants. Currently, there are no approved drugs targeting a dysfunctional intestinal barrier, which emphasizes a significant medical need. One candidate drug reported to regulate intestinal mucosal permeability is melatonin. However, it is still unclear if its effect is primarily receptor mediated or antioxidative, and if it is associated with enteric neural pathways. The aim of this rat intestinal perfusion study was to investigate the mechanisms of melatonin and nicotinic acetylcholine receptors on the increase in intestinal mucosal clearance of 51Cr-labeled ethylenediaminetetraacetate induced by 15 min luminal exposure to the anionic surfactant, sodium dodecyl sulfate. Our results show that melatonin abolished the surfactant-induced increase in intestinal permeability and that this effect was inhibited by luzindole, a melatonin receptor antagonist. In addition, mecamylamine, an antagonist of nicotinic acetylcholine receptors, reduced the surfactant-induced increase in mucosal permeability, using a signaling pathway not influenced by melatonin receptor activation. In conclusion, our results support melatonin as a potentially potent candidate for the oral treatment of a compromised intestinal mucosal barrier, and that its protective effect is primarily receptor-mediated.

Effect of paracellular permeation enhancers on intestinal permeability of two peptide drugs, enalaprilat and hexarelin, in rats.

Transcellular permeation enhancers are known to increase the intestinal permeability of enalaprilat, a 349 Da peptide, but not hexarelin (887 Da). The primary aim of this paper was to investigate if paracellular permeability enhancers affected the intestinal permeation of the two peptides. This was investigated using the rat single-pass intestinal perfusion model with concomitant blood sampling. These luminal compositions included two paracellular permeation enhancers, chitosan (5 mg/mL) and ethylenediaminetetraacetate (EDTA, 1 and 5 mg/mL), as well as low luminal tonicity (100 mOsm) with or without lidocaine. Effects were evaluated by the change in lumen-to-blood permeability of hexarelin and enalaprilat, and the blood-to-lumen clearance of 51chromium-labeled EDTA (CLCr-EDTA), a clinical marker for mucosal barrier integrity. The two paracellular permeation enhancers increased the mucosal permeability of both peptide drugs to a similar extent. The data in this study suggests that the potential for paracellular permeability enhancers to increase intestinal absorption of hydrophilic peptides with low molecular mass is greater than for those with transcellular mechanism-of-action. Further, the mucosal blood-to-lumen flux of 51Cr-EDTA was increased by the two paracellular permeation enhancers and by luminal hypotonicity. In contrast, luminal hypotonicity did not affect the lumen-to-blood transport of enalaprilat and hexarelin. This suggests that hypotonicity affects paracellular solute transport primarily in the mucosal crypt region, as this area is protected from luminal contents by a constant water flow from the crypts.

Physicochemical Characterization and Biopharmaceutical Evaluation of ZWF: A Novel Anticancer Drug for the Treatment of Non-small Cell Lung Cancer.

The orally available novel small molecule drug ZWF is under preclinical development for an anticancer purpose. The present study aimed to assess the viability of developing ZWF as a form of oral formulation for clinical application based on the principles of biopharmaceutics and pharmacokinetics. The crucial physicochemical properties of ZWF were determined by in vitro assays. The in situ gastrointestinal absorption characteristics and in vivo pharmacokinetic behaviors of ZWF in rats were characterized. The solubility of ZWF showed a highly pH-dependent profile, decreasing from 25,392.89 to 20.48 µg/mL as the solution pH increased from 1.0 to 5.8. In PBS with a pH of 1.0 to 5.8, the LogP value of ZWF ranged from -2.35 to 2.20 and was gradually increased as the pH value increased. ZWF was partially absorbed in the stomach, and the favorable absorption sites were the duodenum, jejunum, and ileum. Pharmacokinetic studies showed that the AUC(0-t) and Cmax values of ZWF after its oral administration as a suspension prepared with 0.5% CMC-Na were increased by 18.97% and 40% than that with normal saline, providing a model oral formulation of ZWF with ideal bioavailability and system exposure in rats. From the perspective of oral absorption, ZWF possessed appealing qualities as a drug candidate and could be prepared as an oral preparation for clinical application. The present study has established a fundamental foundation for the development and quality evaluation of the ZWF oral formulations.

Glycyrrhizic acid-based self-assembled micelles for improving oral bioavailability of paeoniflorin.

BACKGROUND: Paeoniflorin (Pae), a water-soluble monoterpene glucoside, has high potential clinical value in autoimmune and inflammatory diseases. However, the extremely low oral bioavailability of Pae (approximately 3%-4%) limits its formulation development and clinical application. This study aimed to develop micelles using the glycyrrhizic acid (GL) as the carrier to improve the oral absorption of Pae. METHODS: Pae-loaded GL micelles were prepared by the ultrasonic dispersion method and its formulation was optimized by single-factor tests. Characterizations of Pae-loaded GL micelles including particle size, zeta potential, entrapment efficiency (EE), drug loading (DL), morphology, and drug release in vitro were carried out. The single-pass intestinal perfusion and pharmacokinetic studies of Pae-loaded GL micelles were also evaluated in rats and compared with Pae solution and the mixed solution of Pae and GL. RESULTS: The optimized Pae-loaded GL micelles had EE of (42.21 ± 0.89)%, particle size of (58.89 ± 4.24) nm with PDI of (0.194 ± 0.010), zeta potential of (-24.40 ± 1.90) mV. Pae-loaded GL micelles showed a nearly spherical shape under TEM. Drug release of micelles demonstrated a delayed drug release compared to Pae solution. The single-pass intestinal perfusion study showed a significantly higher permeability of Pae in duodenum (p < 0.05), jejunum (p < 0.05), ileum (p < 0.01) and colon (p < 0.01) intestine after perfusion of Pae-loaded GL micelles as compared to Pae solution. The in vivo pharmacokinetics demonstrated that the Cmax and AUC0-t values of Pae-loaded GL micelles were approximately 2.18- and 3.64-fold superior than the Pae solution. CONCLUSION: These results suggested GL could be a potential carrier for the oral delivery of Pae.

Panax quinquefolium saponin liposomes prepared by passive drug loading for improving intestinal absorption.

Panax quinquefolium saponin (PQS) composed of 45% pseudo-ginsenoside F11 (PF11), is a natural mixture of sterol compounds obtained from the American ginseng plant, having numerous promising benefits for health. However, low solubility and permeability limit the development of PQS as a therapeutic agent for oral administration. In this study, PQS liposomes (PQS-Lips) were prepared by thin layer hydration, an in situ single-pass intestinal perfusion (SPIP) model was used to verify the improvement of membrane permeability of PQS-Lips. PQS-Lips had a high encapsulation efficiency (EE) of 65%∼70%, a particle size about 100.0 nm, and a zeta potential of -60 mV with regular spherical surface. FTIR and DSC showed the PQS in liposomes were amorphous, indicating that hydrogen bonds formed between one or several hydroxyl groups in PQS and C-O group at the phospholipid polar terminal. In addition, PQS-Lips showed sustained release in vitro than PQS at pH 1.2 and pH 6.8, and PQS-Lips had good stability in simulated gastric and intestinal fluid. Then, the absorption rate (K a) and effective permeability coefficient (P eff) of PQS-Lips in the whole small intestine were significantly higher than those in PQS solution (PQS-Sol), which proved that the PQS-Lips could significantly increase the membrane permeability of PQS and promote its absorption in the small intestine. From the experimental results, it could be known that liposome technology could effectively improve the absorption of PQS in the small intestine.

Prevention of Rat Intestinal Injury with a Drug Combination of Melatonin and Misoprostol.

A healthy intestinal barrier prevents uptake of allergens and toxins, whereas intestinal permeability increases following chemotherapy and in many gastrointestinal and systemic diseases and disorders. Currently, there are no approved drugs that target and repair the intestinal epithelial barrier while there is a medical need for such treatment in gastrointestinal and related conditions. The objective of this single-pass intestinal perfusion study in rats was to investigate the preventive cytoprotective effect of three mucosal protective drugs-melatonin, misoprostol, and teduglutide-with different mechanisms of action on an acute jejunal injury induced by exposing the intestine for 15 min to the anionic surfactant, sodium dodecyl sulfate (SDS). The effect was evaluated by monitoring intestinal clearance of 51Cr-labeled ethylenediaminetetraacetate and intestinal histology before, during, and after luminal exposure to SDS. Our results showed that separate pharmacological pretreatments with luminal misoprostol and melatonin reduced acute SDS-induced intestinal injury by 47% and 58%, respectively, while their use in combination abolished this injury. This data supports further development of drug combinations for oral treatments of conditions and disorders related to a dysregulated or compromised mucosal epithelial barrier.